Preeclampsia (PE) is driven by placental dysfunction, where oxidative stress triggers mitochondrial damage. Damaged mitochondria, in turn, activate the NLRP3 inflammasome, leading to cell pyroptosis and exacerbating placental injury. Kaempferol (KAE), a natural flavonol with antioxidant properties, whether it acts by enhancing mitochondrial clearance to interrupt this damaging cycle, remains unknown. We employed an L-NAME-induced PE rat model and a cellular hypoxia/reoxygenation model using HTR-8/SVneo trophoblasts. KAE's effects were evaluated by monitoring clinical symptoms, placental histology, oxidative stress (DHE staining, MitoSOX), and key protein expression (Western blot, ELISA). The involvement of mitophagy was assessed through detection of PINK1 and Parkin. STAT3 subcellular localization was examined by fractionation, and its functional role was validated using STAT3 siRNA knockdown. Pyroptosis was evaluated by GSDMD-N cleavage, LDH release assay, and propidium iodide (PI) uptake. The specific roles of STAT3 signaling and mitophagy in the therapeutic effects of KAE were investigated using Stattic (STAT3 inhibitor) and Mdivi-1 (mitophagy inhibitor). KAE treatment dose dependently alleviated maternal hypertension, proteinuria, and fetal growth restriction in PE rats. Mechanistically, KAE reduced oxidative stress, restored autophagy flux (increased LC3-Ⅱ/LC3-Ⅰ; decreased p62), upregulated mitophagy-specific markers PINK1 and Parkin, promoted STAT3 phosphorylation and its mitochondrial translocation, and suppressed NLRP3 inflammasome activation and pyroptosis. KAE promoted STAT3 phosphorylation. In vitro, the protective effects of KAE on cell function were reversed by Stattic and Mdivi-1. Stattic blocked KAE's action on STAT3, mitophagy, and pyroptosis, while Mdivi-1 only reversed its effects on mitophagy and downstream pyroptosis without affecting STAT3 activation. STAT3 knockdown confirmed its essential role in KAE-induced mitophagy enhancement and pyroptosis suppression. KAE ameliorates PE through a STAT3-associated mechanism involving enhanced mitophagy, thereby inhibiting NLRP3-driven pyroptosis and improving trophoblast function. This study identifies a STAT3-associated mitophagy pathway as a potential therapeutic target in PE.
